In mammals, extracellular Ca2+ is under rigid homeostatic control with the serum calcium concentration strictly maintained at a concentration of approximately 1.1 to 1.3 mM in a healthy mammal. The extracellular Ca2+ homeostasis depends on integrated regulation of Ca2+ fluxes with respect to the intestine, kidneys and bone. The extracellular Ca2+ regulates various processes such as blood coagulation, nerve and muscle excitability, and normal bone homeostasis. When the Ca2+ serum concentration decreases by 50% tetania occurs, and when the Ca2+ serum concentration increases by 50% consciousness is clouded, in both instances a potentially life threatening circumstance. Extracellular Ca2+ also inhibits the secretion of parathyroid hormone (PTH) from parathyroid cells, inhibits bone resorption by osteoclasts, stimulates secretion of calcitonin from C-cells and is involved in re-absorption and excretion in the kidney.
The extracellular calcium-sensing receptor (CaSR) is a hormone-like receptor, more particularly a plasma membrane-bound G protein-coupled receptor (GPCR) that belongs to family 3 of the GPCR superfamily. Family 3 of the GPCR superfamily includes metabotropic glutamate receptors (mGluRs), γ-aminobutyric acid B-type receptors (GABABRS) as well as putative pheromone and taste receptors. The CaSR has a large extracellular domain exhibiting “Venus flytrap” topology, a seven-transmembrane domain and a relatively large cytoplasmic domain. Human CaSR consists of 1078 amino acids and shares 93% amino acid homology with bovine CaSR. The CaSR senses and is activated by changes in extracellular Ca2+ levels. The presence of CaSR on certain specialized cells enables those Ca2+-sensing cells to respond to changes in extracellular Ca2+ concentration. Examples of Ca2+-sensing cells include the parathyroid-secreting cells of the parathyroid gland, the calcitonin-secreting C cells of the thyroid gland and certain cells in the kidney. In addition, the CaSR has been found in a wide variety of other tissues including intestine, bone, bone marrow, brain, skin, pancreas, lung and heart.
The CaSR on the surface of parathyroid chief cells is the primary entity that regulates secretion of PTH from parathyroid cells. Activation of the CaSR on parathyroid chief cells by extracellular Ca2+ suppresses PTH production and secretion, inhibits parathyroid cellular proliferation and likely inhibits PTH gene expression. The CaSR on the surface of the calcitonin-secreting C cells of the thyroid gland mediate the stimulatory action of high extracellular Ca2+ concentration on calcitonin secretion, thereby increasing the circulating level of the Ca2+-lowering hormone calcitonin. The CaSR is also present in the kidney, along much of the nephrons and at the basolateral surface in the cortical thick ascending limb. In the basolateral surface in the cortical thick ascending limb the CaSR is thought to mediate high Ca2+-induced inhibition of the tubular re-absorption of Ca2+ and magnesium. A reduction of renal cortical synthesis of 1,25(OH)2 vitamin D and polyuria with dilute urine are partially the result of hypercalcaemic activation of the CaSR in the nephron.
PTH is the primary endocrine hormone regulating Ca2+ homeostasis in the blood and extracellular fluids. PTH, by acting on bone and kidney cells, increases the level of Ca2+ in the plasma. This increase in plasma Ca2+ concentration then acts as a negative feedback signal, thereby depressing PTH secretion. The reciprocal relationship between extracellular Ca2+ and PTH secretion forms an important mechanism for maintaining bodily Ca2+ homeostasis. PTH has been found to increase bone turnover, but the overall effect on bone is dependent on temporal changes in circulating levels of PTH. Sustained elevations in circulating plasma PTH levels, as occurs in hyperparathyroidism, have been found to result in a net catabolic effect on bone. By contrast, transient increases in plasma PTH levels, achieved by daily or near daily injection of exogenous hormone, have been found to exhibit a net anabolic effect on bone. The effect of PTH on bone is likely due to PTH being able to induce a rapid release of calcium from bone and mediate other changes by acting directly on osteoblasts and indirectly on osteoclasts. PTH affects cellular metabolic activity, ion transport, cell shape, gene transcriptional activity and secretion of proteases in osteoblasts. Also, PTH stimulates the production of RANKL, a protein that plays a crucial role in osteoclast differentiation and activity.
Various compounds are known to modulate the effects of extracellular Ca2+ on the CaSR. Calcimimetics are agents that act as allosteric modulators of the CaSR that increase the sensitivity of the CaSR to activation by extracellular Ca2+. Calcilytics, or calcium receptor antagonists, are agents that act as modulators of the CaSR that inhibit CaSR activity. This inhibition of the CaSR activity results in a decrease of one or more CaSR activities that are evoked by extracellular Ca2+.
Certain urea derivatives, such as those disclosed in PCT International Publication WO 02/059102, are described as having calcimimetic activity. In addition, certain phenylalkylamine derivatives have been identified as calcimimetics. Phenylalkylamine calcimimetic compounds include (R)—N-(1-(3-methoxyphenyl)ethyl)-3-phenylpropan-1-amine hydrochloride (NPS-467); (R)-3-(2-chlorophenyl)-N-(1-(3-methoxyphenyl)ethyl)propan-1-amine hydrochloride (NPS R-568, tecalcet hydrochloride) and (R)-(−)-N-(1-(naphthalen-1-yl)ethyl)-3-(3-(trifluoromethyl)phenyl)propan-1-amine hydrochloride (NPS-1493, cinacalcet hydrochloride). Cinacalcet hydrochloride and uses thereof are disclosed in U.S. Pat. Nos. 6,011,068; 6,031,003; 6,211,244 and 6,313,146. Cinacalcet hydrochloride is marketed as Sensipar® and Minpara® in the U.S. and Europe, respectively, and is indicated for the treatment of secondary hyperparathyroidism in patients with chronic kidney disease on dialysis and for hypercalcemia in patients with parathyroid carcinoma.
Calcilytics, or calcium receptor antagonists, have been described in various publications such as PCT International Publication Nos. WO 93/04373; WO 94/18959; WO 95/11211; WO 97/37967; WO 98/44925; WO 98/45255; WO 99/51241; WO 99/51569; WO 00/45816; WO 02/14259; WO 02/38106; WO 2004/041755; and WO 2005/030746; Nemeth, E. F.; Journal of Molecular Endocrinology (2002) 29, 15-21; Kessler, A. et al.; ChemBioChem (2004) 5, 1131; Steddon, S. J. et al.; Lancet (2005) 365, 2237-2239; and Shcherbakova, I.; et al.; Bioorganic & Medicinal Chemistry Letters (2005) 15, 1557-1560.
Calcium receptor antagonists are useful in the treatment of various disease states characterized by abnormal levels of one or more components, e.g., polypeptides such as hormones, enzymes or growth factors, the expression and/or secretion of which is regulated or affected by activity at one or more CaSR. Target diseases or disorders for calcium receptor antagonists include diseases involving abnormal bone and mineral homeostasis. Abnormal calcium homeostasis is characterized by one or more of the following activities: an abnormal increase or decrease in serum calcium; an abnormal increase or decrease in urinary excretion of calcium; an abnormal increase or decrease in bone calcium levels (for example, as assessed by bone mineral density measurements); an abnormal absorption of dietary calcium; an abnormal increase or decrease in the production and/or release of messengers which affect serum calcium levels such as PTH and calcitonin; and an abnormal change in the response elicited by messengers which affect serum calcium levels.
The novel calcium receptor antagonists of this invention are useful in the treatment of diseases associated with abnormal bone or mineral homeostasis. Thus, these calcium receptor antagonists are useful in the treatment of hypoparathyroidism, osteoporosis, osteopenia, periodontal disease, bone fracture, osteoarthritis, rheumatoid arthritis, Paget's disease, humoral hypercalcemia associated with malignancy.